Parkinson's disease (PD) is one of the most common neuro-degenerative diseases which affect the elderly.
The following is a representative list of references which discuss Parkinson's disease and therapeutic strategies:
1. de Rijk M C, Breteler M M B, Graveland G A, et al. Prevalence of Parkinson's disease in the elderly: The Rotterdam study. Neurol. 1995; 45:2143-2146. PA0 2. Bennet D A, Beckett L A, Murray A M, et al. Prevalence of Parkinsonian signs and associated mortality in a community population of older people. N Engl. J. Med. 1996; 334(2):71-76. PA0 3. Hornykiewicz O, Kish S J. Biochemical pathophysiology of Parkinson's disease. Adv Neurol. 1986; 45:19-34. PA0 4. Leenders K L, Salmon E P, Tyrrel P, et al. The nigrostriatal dopaminergic system assessed in vivo by positron emission tomography in healthy volunteer subjects and patients with Parkinson's disease. Arch Neurol. 1990; 47:1290-1298. PA0 5. LeWitt P A. Levodopa Therapeutics: New treatment strategies. Neurology 1993; 43(suppl. 6):S31-S37. PA0 6. Peppe A, Dambrosia J M, Chase T N. Risk factors for motor response complications in L-Dopa treated parkinsonian patients. Adv Neurol 1993; 60:698-702. PA0 7. Chase T N, Mouradian M M, Engber T M. Motor response complications and the function of striatal efferent systems. Neurology 1993; 43(suppl. 6): S23-S27. PA0 8. Doller H J, Connor J D. Changes in neostriatal dopamine concentrations in response to levodopa infusions. J Neurochem 1980; 34:1264-1269. PA0 9. Spencer S E, Wooten G F. Altered pharmacokinetics of L-dopa metabolism in rat striatum deprived of dopaminergic innervation. Neurology 1984; 34:1105-1108. PA0 10. Spencer S E, Wooten G F. Pharmacologic effects of L-dopa are not closely linked temporally to striatal dopamine concentration. Neurology 1984; 34:1609-1611. PA0 11. Hardie R J, Malcolm S L, Lees A J, et al. The pharmacokinetics of intravenous and oral levodopa in Parkinson's patients who exhibit on-off fluctuations Br J Clin Pharmacol 1986; 22:421-436. PA0 12. Fabbrini G, Juncos J, Mouradian M M, et al. Levodopa pharmacokinetic mechanisms and motor fluctuations in Parkinson's disease. Ann Neurol 1987; 21:370-376. PA0 13. Nutt J G, Woodward W R, Hammerstad J P, et al. The "on-off" phenomenon in Parkinson's disease: relation to levodopa absorption and transport. N Engl J Med 1984, 310:483-488. PA0 14. Shoulson I, Glaubiger G A, Chase T N. On-off response: clinical and biochemical correlations during oral and intravenous levodopa administration in parkinsonian patients. Neurology 1975; 25:1144-1148. PA0 15. Quinn N, Parkes J D, Marsden C D. Control of on/off phenomenon by continuous intravenous infusion of levodopa. Neurology 1984; 34:1131-1136. PA0 16. Schuh L A, Bennet J P. Suppression of dyskinesias in advanced Parkinson's disease. I. Continuous intravenous levodopa shifts dose-response for production of dyskinesias but not for relief of parkinsonism in patients with advanced Parkinson's disease. Neurology 1993; 43:1545-1550. PA0 17. Sage J I, McHale DM, Sonsulla P, et al. Continuous levodopa infusion to treat complex dystonia in Parkinson's disease. Neurology 1989; 39:888-891. PA0 18. Schelosky L, Poewe W. Current strategies in the drug treatment of advanced Parkinson's disease--new modes of dopamine substitution. Acta neurol Scand 1993; 87(suppl. 146):46-49. PA0 19. Nutt J G, Woodward W R. Levodopa pharmacokinetics and pharmacodynamics in fluctuating parkinsonian patients. Neurology 1986; 36:739-744. PA0 20. Nelson M V, Berchou R C, LeWitt P A, et al. Pharmacodynamic modeling of concentration-effect relationship after controlled-release carbidopa/levodopa (Sinemet CR-4) in Parkinson's disease. Neurology 1990; 40:70-74. PA0 21. Bredberg E, Nilson D, Johansson K, et al. Intraduodenal infusion of a water-based levodopa dispersion for optimisation of the therapeutic effect in sever Parkinson's disease. Eur J Clin Pharmacol 1993; 45:117-122. PA0 22. Mouradian M M, Juncos J L, Fabbrini G, et al. Motor fluctuations in Parkinson's disease: central pathophysiological mechanisms. Part II. Ann Neurol 1988; 24;372-378. PA0 23. Sage J I, Mark M H. The rationale for continuous dopaminergic stimulation in patients with Parkinson's disease. Neurology 1992; 42(Suppl. 1):23-28. PA0 24. Chase T N Baronti F, Fabbrini G, et al. Rational for continuous dopaminometic therapy of Parkinson's disease. Neurology 1989; 39(Suppl. 2):7-10. PA0 25. Sage J I, Mark M I. Basic mechanisms of motor fluctuations. Neurology 1994; 44(Suppl. 6):S10-S14. PA0 26. Sage J L, Trooskin S, Sonsalla P K, et al. Experience with continuous enteral levodopa infusions in the treatment of 9 patients with advanced Parkinson's disease. Neurology 1989; 39(Suppl. 2):60-63. PA0 27. Mouradian M M, Heuser I J E, Baronti F, et al. Modification of central dopaminergic mechanisms by continuous levodopa therapy for advanced Parkinson's disease. Ann Neurol 1990; 27:18-23. PA0 28. Bravi D, Mouradian M M, Roberts J W, et al. End-of-dose dystonia in Parkinson's disease. Neurology 1993; 43:2130-2131. PA0 29. Tanner C M, Melamed E, Lees A J. Managing motor fluctuations, dyskinesias and other adverse effects in Parkinson's disease. Neurology 1994; 44(Suppl. 1):S12-S16. PA0 30. Joseph King Ching Tsui. Future Treatment of Parkinson's disease. Can J Neurol Science 1992; 19:160-162. PA0 31. Djaldetti R, Atlas D, Melamed E. Subcutaneous injections of levodopa-ethylester: A potential novel rescue therapy for response fluctuations in patients with Parkinson's disease (Abst). Neurology 1995; 45(Suppl. 4):415S. PA0 32. LeWitt P A. In: Levodopa controlled-release preparations. Neurology 1993, 43(Suppl. 6)S38-S40. PA0 33. Koller W C, and Pahwa R. Treating motor fluctuations with controlled-release levodopa preparations. Neurology 1994; 44(Suppl. 6):S23-S28. PA0 1. CR preparations have a delayed onset. The peak effect of Sinemet CR (commercially available from Merck Sharp and Dohme Research Laboratories) was shown to occur an hour later than that of the conventional Sinemet (Refs. 18, 32). PA0 2. The bioavailability of the CR preparations is low (Refs. 18, 32). The low bioavailability is explained by the variable properties of the gastro-intestinal tracts (Ref. 33). PA0 3. Reduced reliability and predictability of the clinical response (Refs. 32, 33). PA0 4. According to many investigators, the CR preparations do not provide the same favorable effect which was demonstrated by a continuous administration of LD such as an IV infusion (e.g., Refs. 5, 15, 18). PA0 5. Sclerosis of the peripheral veins occurs frequently during an IV infusion of LD (Ref. 5). PA0 6. A gastrostom-duodenal tube or an esophageal catheter is very unpleasant.
The prevalence of diagnosed PD in the population above the age of 55 is about 1.4% and it increases with age (Ref. 1). Moreover, Parkinsonian signs in the elderly are estimated to occur in 30% of the population over the age of 65 (Ref. 2). Although PD is considered a multisystem disease, it is mainly a movement disorder caused by a continuous, long lasting degeneration of the dopaminergic neurons that are located in the mesencephalic substantia nigra pars compacta. PD becomes symptomatic only after degeneration of about 60-80% of these dopaminergic neurons, or after the loss of about 90% of the striatal dopamine (Refs. 3, 4). Dopamine (DA), which is produced within the substantia nigra, reaches the striatum via the nigro-striatal tract and is released at the striatal synapses. DA deficiency in the striatum, due to the degeneration of the dopaminergic neurons in the substantia nigra, is considered to be the cause of PD. Consequently, the most effective treatment of PD is Levodopa (LD), which is converted to DA by enzymatic decarboxylation. Inhibition of the peripheral aromatic amino acid decarboxylase by carbidopa (an inhibitor that cannot penetrate the blood-brain-barrier) improves dramatically the results of the treatment. However, the currently available LD preparations are effective only for a relatively short period and may be even deleterious under certain conditions (as will be explained below).
Administration of LD is especially successful during early stages of the disease. Adverse effects of LD, such as dyskinesias and hallucinations that occur at early stages of the disease are dose-dependent. These adverse effects are attributed to hypersensitivity of denervated striatal dopaminergic receptors to exogenous doparmine (Ref. 5). At late stages of the disease additional types of adverse effects appear as the response to LD becomes unpredictable, fluctuative and the duration of the response is reduced. Motor fluctuations appear after about 4-5 years from the introduction of LD therapy in 24%-84% of the patients (Ref. 6). The most common and disabling motor complications are: 1) "wearing-off" fluctuations; 2) "on-off" fluctuations and 3) peak-dose dyskinesias (Ref. 7).
The "wearing-off" effect means a reduction in the duration of the beneficial effect after each administration of LD. During this period, LD must be administered more frequently than before, a problem which severely affects the quality of life of the patient. Complications such as "wearing off" may arise due to limitation of storage capacity of DA in the CNS (Refs. 5, 8-10). When neuronal DA storage is reduced, the clinical state of the patients becomes fully dependent on the fluctuating blood level of LD. Since the normal half-life of LD in the circulation is 1-2 hours (Refs. 11-13), LD should be administered at this stage more frequently and the effect is fluctuative. Moreover, with the currently available oral preparations, the blood level of LD is a function of the rate of absorption from the gastrointestinal tract, which is irregular and uncontrollable. The resulting fluctuations of the LD blood levels contribute further to the instability of the effect. A continuous drug delivery, which maintains a constant blood level of LD, has been shown to improve significantly the clinical state of the fluctuating parkinsonian patients (Refs. 13-18). In this regard, it has been reported that therapeutic effects of LD were noticed when LD plasma levels reached 300-800 ng/ml (Refs. 19-21).
The "on-off" fluctuations are inconsistent transitions between a hypokinetic parkinsonian state (the "off" state) and a hyperkinetic state (the "on" state). The clinical state of these patients is highly correlated with the plasma concentration of LD (Refs. 5, 20). It is thought that these fluctuations result from a narrowing of the therapeutic window of LD. An intermittent administration of LD, given for a long period, is considered to be one of the major causes of the reduction of the therapeutic window (Refs. 22, 23) and consequently leads to the motor fluctuations (Refs. 23-25). On the other hand, a continuous infusion of LD has been shown to increase the therapeutic window and to reduce the "on-off" fluctuations (Refs. 25-27). Moreover, during a continuous administration, the blood levels of LD which are needed to keep the patient at the "on" state gradually decrease (Ref. 21).
Peak-dose dyskinesia is a common advanced motor complication which occurs when the blood level of LD rises to its peak. This complication is observed in advanced stages of the disease when patients show a very steep dose-response curve. Under such circumstances, small shifts in circulating LD levels, and thus in cerebral DA, induce major swings in the clinical state (Ref. 7). In this stage of the disease, a continuous administration that keeps the circulating LD level constant, may prevent the dyskinesias. Moreover, these kinds of dyskinesias, like the "on-off" dyskinesia, may not develop during a continuous administration of LD (Refs. 7, 16, 17, 28, 29).
All these findings and observations clearly suggest that a continuous delivery of LD is advantageous over an intermittent administration. Persistent attempts have been made in effort to develop a sustained delivery of LD (Refs. 30, 31). Strategies to improve the clinical results of intermittent LD administration include controlled release (CR) preparations and pump-delivery of LD. However, the existing preparations and devices suffer from several disadvantages as follows:
To overcome these disadvantages, and yet to administer LD in a continuous manner, an alternative method of drug delivery is needed.